Major depressive episodes contribute substantially to morbidity and mortality in bipolar disorder. While multiple medications have demonstrated efficacy for treating these episodes, a majority of patients do not reach complete symptomatic remission or have difficulty tolerating these medications. Studies of the mechanism of action of treatments known to be effective in bipolar may provide new treatment targets. Work by our group and others strongly implicates Wnt/GSK3 signaling in the mechanism of action of lithium, which remains a first-line treatment for bipolar depression as well as prevention of recurrence. We therefore have utilized high-throughput cell-based screening in neuronal cells to identify compounds that showed potential additivity or synergy with lithium in terms of effects on Wnt/GSK3 signaling. Among the active F.D.A.-approved drugs with safety profiles compatible with long-term use, we identified multiple statins that acted synergistically with Wnt3a treatment and show further additivity with lithium treatment, including simvastatin, one of the most potent statins known to be capable of crossing the blood-brain barrier. We have validated 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase as the relevant target. Statins have not been directly examined in the treatment of bipolar disorder. A recent rodent study found evidence that a statin augmented the antidepressant-like effects with fluoxetine. Intriguingly, multiple population-based studies also suggest that statins may be associated with a statistically significant decrease in depressive symptoms, and a decrease in the likelihood of adverse psychiatric outcomes. Another study examining statin treatment of dementia indicated a decrease in depressive symptoms compared to placebo. We now propose to conduct a randomized, double-blind, placebo-controlled, proof-of-concept investigation of simvastatin as add-on treatment to lithium in outpatients with bipolar I disorder in a major depressive episode. In parallel, we will collect fibroblasts and derive induced pluripotent stem cells (iPSCs) and neuronal progenitor (NP) cells. The function of the Wnt signaling pathway in patient-specific iPSC-derived NP cells will then be quantified in cell-based assays, with and without treatment with lithium and simvastatin, to enable examination of the association between Wnt/GSK3 signalling and magnitude of improvement in depressive symptoms. These experiments are expected to serve as a crucial first step in the development of new bipolar pharmacotherapies. By predicting the benefit of an adjunctive therapy for bipolar disorder based upon its effects on Wnt/GSK3 signaling pathway and attempting to correlate these responses using patient-specific neuronal cell models, our proposed study will provide a critical test of the importance of Wnt/GSK3 signaling in regulating neuroplasticity in bipolar disorder and depression. At a minimum, these studies will also provide a well-phenotyped, patient-derived cellular resource for future investigation of lithium response and bipolar disorder that can be applied in future studies toward high-throughput screening for lithium-like drugs.